The role of p17 protein in development of HIV associated neurocognitive disorder

Zeinolabediny, Yasmin (2016) The role of p17 protein in development of HIV associated neurocognitive disorder. Doctoral thesis (PhD), Manchester Metropolitan University.

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Abstract

HIV-associated neurocognitive disorder in HIV patients substantially reduces their quality of life. We hypothesised that the HIV matrix protein, p17, already linked to tumour promotion and aberrant angiogenesis could contribute to neurological decline and cellular dysfunction within the brain and aimed here to confirm this. The experimental design was formulated to test the direct neurodegenerative capacity of p17 protein on relevant brain cells, both in vitro and in vivo to ascertain the potential of p17 within the brain to encourage neurodegenerative processes and to confirm that p17 was present in the brain of infected individuals. In vitro cell culture experiments identified cellular signalling induced by p17 within brain cells. I characterised the effects of hippocampal CA1 injection of p17 on histological appearance of brain sections following the analysis of the animals by our collaborators- behaviour, cognitive function and memory. Histological expression of p17 in tissue from three HIV patients who died from stroke was determined. Cell signalling pathways potentially associated with neurodegenerative signalling or aberrant angiogenesis were studied by Western blotting. p17 increased phosphorylation of ERK1/2, IRS-1 and EGFR in endothelial cells, blocking cell signalling and angiogenesis via an inhibitor peptide of EGFR. In neurons, p17 induced the phosphorylation of ERK1/2, Tau, FAK and IRS-1. Cognitive function and behavioural deficiencies after p17 injection were mimicked by demonstration that it localised in ventricular tracts, cortical microvessels and neurons. p17 formed β-amyloid/prion-like protein fibrillar aggregates, suggesting a pathogenic direct capability similar to that of β-amyloid. P17 was also identified in macrophages, microvessels, neurons and amyloid-beta (Aβ)-positive plaques in HIV-infected human brain sections. This work supports the involvement of p17 in initiating/perpetuating neurodegenerative pathophysiology associated with cognitive decline. Key words: P17, HIV-associated neurocognitive decline, angiogenesis, fibrillary, signalling.